1. Field of the Invention
The present invention relates to a biodegradable multi-block copolymer having an improved release profile and control of the release rate for various drugs. Particularly, the present invention provides a multi-block copolymer comprising ABA-type tri-block copolymers wherein the A block is polyethyleneoxide and the B-block is a polypropyleneoxide or polybutyleneoxide block, and wherein the resulting PEO-PPO (or PBO)-PEO blocks are connected through dicarboxylic linkages which can be hydrolyzed in the living body.
2. Description of the Related Art
Hydrogels have biocompatible properties and thus have been widely used as drug carriers. A therapeutic agent is entrapped within the crosslinked hydrogel matrix and upon release passes through interstices in the matrix.
Early drug delivery systems used gels having thermoplastic properties. The thermoplastic system involved the formation of a polymeric solution in solvents. Before injection into the body, a drug was added to the polymeric solution. After injection the polymeric solution quickly formed a gel by exposure to body fluids. However, the early drug delivery systems had problems in that they could be toxic and irritating to the body due to the presence of the organic solvent.
Recently, a gel drug delivery system using aqueous solutions has been developed. The system uses a block copolymer which is composed of polyethylene oxide and polypropylene oxide. The polyethylene oxide and polypropylene oxide copolymers, when at sufficient concentration and temperature, absorb water to form a gel (U.S. Pat. Nos. 4,188,373, 4,478,822 and 4,474,751). An example of the polymeric solution is known as a poloxamer and is commercially available. The poloxamer is a tri-block copolymer of PEO-PPO-PEO wherein PEO is a polyethylene oxide block and PPO is a polypropylene oxide block (PPO). The poloxamer has a molecular weight ranging from 9,840 to 14,600 Daltons. However, the poloxamer-based gel is non-biodegradable. In order to undergo phase transition under physiological conditions, a poloxamer polymer solution having a concentration of more than 18 to 20% is necessary. However, such a concentrated solution has a very high viscosity in the liquid phase and thereby may induce unfavorable reactions in the living body. Although when injected into a living body, it is quickly transformed into a gel, the gel status can only be maintained for several hours and therefore it has limited application as a drug delivery system.
In order to solve these problems, Sosnik et al. synthesized the compound of formula 1, wherein poloxamer 407 blocks are connected by a urethane linkage by reacting poloxamer 407 and hexamethylene diisocyanate (Winter Symposium & 11th International Symposium on Recent Advances in Drug Delivery Systems, 2003 Controlled Release Society, #117)).[PEO—PPO—PEO—CO—NH—(CH2)6—NCO]p, wherein p is 4.  Chemical formula 1
It is disclosed in Sosnik that the compound with the chemical formula 1 has a viscosity several times higher than poloxamer 407 in the case of a 17% aqueous solution and a significantly longer time in maintaining its gel status at high temperatures. However, there are problems with the polymer in that it is non-biodegradable and has a molecular weight of more than 50,000 Daltons and thus excretion from the body is difficult.
X. Zhao et al. discloses a biodegradable polymeric composition including the poloxamer 407 of chemical formula 2 (30th annual meeting and exhibition of the controlled release society, Glasgow, Scotland, Jul. 19-23, 2003). In preparation of the polymer, a poloxamer 407 is reacted with disuccincimidyl carbonate (DSC), so that poloxamer 407 blocks are connected through carbonate linkages as shown in Chemical Formula 2.HO—[PEO—PPO—PEO—C(═O)—O]n—H, wherein the average number of n is 3.   Chemical formula 2
U.S. Patent Application No. 20030187148 discloses a polymeric composition wherein poly(hydroxyl carboxylic acid) blocks are introduced into both terminal ends of poloxamer 407 and the resulting penta-blocks are chain-extended through a HDI (hexamethylene diisocyanate) linker. However, the polymer is non-biodegradable because urethane linkages are non-biodegradable.
U.S. Pat. No. 6,348,558 discloses a biodegradable polymer wherein at least two polyalkylene oxide oligomers are connected through hydrolytic carbonate linkers.
However, the above disclosed polymers only have hydroxyl groups at the terminal ends and the release rate of a drug from the gel depends only on the diffusion rate which is determined by the viscosity of the gel. Thus it is impossible to control the release rate of the drug.
Therefore, there is a need for a biodegradable polymeric composition which has low toxicity and an improved release profile, and can control of the release rate of various drugs.